The present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as Compound J in the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns a process to prepare the HIV protease inhibitor J from the 4-picolyl piperazine carboxamide 1 via a two-step procedure. The piperazine 1 is condensed with epoxide 2 to afford the coupled product 3. Removal of the acetonide protecting group of 3 directly affords the HIV-1 protease inhibitor J. ##STR1##
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, Compound J therein.
Previously, the synthesis of Compound J and related compounds was accomplished via a 12-step procedure. This procedure is illustrated in EPO 541,168. In prior methods, the HIV protease inhibitor J was prepared by coupling of the epoxide intermediate 2 with the Boc-protected piperazine carboxamide 4 to afford the Boc-protected coupled intermediate 5. Deblocking of 5 then afforded a penultimate Compound 6 which was subjected to picolylation to afford J. The disadvantage with this route is that three chemical steps are necessary to convert the epoxide 2 to J. Thus, after deblocking, a separate picolylation step is necessary to effect conversion to J. Since the more reactive 4-position of the piperazine carboxamide must be protected prior to coupling, the most efficient blocking method for the chiral 2-piperazine-t-butylcarboxamide would be the incorporation of the 3-picolyl moiety at this point. However, it was unexpected that the reaction of piperazine 1 with epoxide 2 would be efficient, since piperazine 1 contains three basic amine functions capable of attacking the epoxide 2. The Boo-protected piperazine 4, however, contains only one basic amine function, and thus it was expected that the coupling of 2 and 4 would be straightforward. ##STR2##
The process of the present invention eliminates one step, an advantage for simplifying the already complex synthesis of Compound J. The present process is shorter and highly efficient.